The Rapidly Evolving Landscape for mRCC

Less than 20 years ago, anindividual with stage IVkidney cancer had fewoptions: interferon or IL-2 immunotherapywith or without upfrontcytoreductive nephrectomy (CRN).

Outcomes with either treatmentwere poor, with a median overallsurvival of 8 months for immunotherapyalone and 14 months whencombined with surgery.1

Around 2006, the field underwentits first major breakthroughwith the introduction of multitargeted tyrosine kinase inhibitors(TKIs). Suddenly, the median overall survival rates doubled tobetween 24 and 30 months depending on other risk factors.

On October 1, 2018, the Nobel Prize in Physiology or Medicinewas jointly awarded to Drs James Allison (USA) and Tasuku Honjo(Japan) for their discoveries of immune checkpoint inhibitors.Sentinel work performed by Dr Allison on the T-cell protein CTLA-4and separately by Dr Honjo on PD-1 expressed on the surface ofT cells led to their discovery of effective cancer therapies by inhibitionof negative immune regulation: in other words, reinvigoratingan antitumor immune response. Just 6 months earlier, the resultsof the Checkmate 214 trial were published. The study showed thatin a population of primarily intermediate- to poor-risk metastaticrenal cell carcinoma (RCC), treatment with the combination of ipilimumab(a CTLA-4 inhibitor) and nivolumab (a PD-1 inhibitor) wasassociated with a nearly 10% complete response rate and a medianoverall survival that had not been reached at the time of publication!

In just over a decade, overall survival for metastatic RCC hasincreased 3- to 4-fold, forcing physicians to reassess the role ofextirpative surgery for stage IV disease. Importantly, the recentlypublished CARMENA trial noted that upfront systemic therapywith an oral TKI was noninferior to CRN followed by systemictherapy in selected intermediate- to poor-risk patients.2 While caveatsexist, the trial demonstrates that refinements in surgical thinkingmust occur in parallel with improvements in systemic therapies.

The speed of the evolving science and therapeutics in RCC isstaggering. Most physicians do not see such incremental benefitsand new treatment paradigms in their entire career, but in kidneycancer, we are seeing incredible progress in only a fraction of ourown careers, and this progress is expected to keep accelerating.